Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002395 (Alzheimer's disease)
 110,584 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Alzheimer's disease, deposits of amyloid beta-protein are apparently derived from intracellular processing of a large precursor protein. We have measured concentrations of this precursor in cerebrospinal fluid (CSF) from six members of a family affected by presenile Alzheimer's disease associated with a point mutation of the precursor gene. One gene carrier with clinical signs of the disorder had low CSF concentrations of the precursor, similar to those of three patients with sporadic Alzheimer's disease subsequently confirmed at necropsy. Two symptom-free gene carriers had CSF precursor concentrations similar to those of non-demented controls, though the value was lower in one, who had deficits revealed on neuropsychological testing, than in the other. These findings suggest that low concentrations of soluble amyloid precursor proteins in the CSF reflect the process that results in amyloid plaque formation and vascular deposition in Alzheimer's disease.
 ...
PMID:Low cerebrospinal-fluid concentrations of soluble amyloid beta-protein precursor in hereditary Alzheimer's disease. 135 85

Alzheimer's disease is a progressive neurodegenerative disorder that affects a significant percentage of elderly individuals. Degenerative nerve cells express atypical proteins, and amyloid is deposited. The hallmark event of Alzheimer's disease is the deposition of amyloid as insoluble fibrous masses in extracellular neuritic plaques and around the walls of cerebral blood vessels. This review will focus on the advances on the knowledge of Alzheimer's amyloid, because it is becoming increasingly clear that the deposition of amyloid on neuritic plaques in the brain represents the earliest and most characteristic pathological feature of Alzheimer's disease. The main component of amyloid is a 4.2-4.5 KDa hydrophobic peptide, named amyloid beta-peptide, that is codified in chromosome 21 as part of a much larger precursor protein. The study of the mechanism by which the amyloid beta-peptide arises from the amyloid precursor protein is very important in order to understand the biological basis of amyloid deposition and its role in Alzheimer's disease.
 ...
PMID:Molecular biology of the amyloid of Alzheimer's disease. An overview. 136 3

Using a monoclonal antibody raised against purified, native, human protease nexin-2/amyloid precursor protein, which recognizes an amino terminal epitope on the amyloid precursor protein and detects all major isoforms of amyloid precursor protein, we examined the localization of the amyloid precursor protein within Alzheimer's and aged control brains. Very light cytoplasmic neuronal amyloid precursor protein staining but no neuritic staining was visible in control brains. In the Alzheimer's brain, we detected numerous amyloid precursor protein-immunopositive neurons with moderate to strong staining in select regions. Many neurons also contained varying levels of discrete granular, intracellular accumulations of amyloid precursor protein, and a few pyramidal neurons in particular appeared completely filled with amyloid precursor protein granules. "Ghost"-like deposits of amyloid precursor protein granules arranged in pyramidal, plaque-like shapes were identified. We detected long, amyloid precursor protein-immunopositive neurites surrounding and entering plaques. Many contained swollen varicosities along their length or ended in bulbous tips. Amyloid precursor protein immunoreactivity in the Alzheimer's brain was primarily present as granular deposits (plaques). The amyloid precursor protein granules do not appear to co-localize within either astrocytes or microglia, as evidenced by double-labeling immunohistochemistry with anti-glial fibrillary acidic protein and anti-leukocyte common antigen antibodies or Rinucus cummunicus agglutin lectin. Amyloid precursor protein could occasionally be detected in blood vessels in Alzheimer's brains. The predominantly neuronal and neuritic localization of amyloid precursor protein immunoreactivity indicates a neuronal source for much of the amyloid precursor protein observed in Alzheimer's disease pathology, and suggests a time-course of plaque development beginning with neuronal amyloid precursor protein accumulation, then deposition into the extracellular space, subsequent processing by astrocytes or microglia, and resulting in beta-amyloid peptide accumulation in plaques.
 ...
PMID:Aggregation of the amyloid precursor protein within degenerating neurons and dystrophic neurites in Alzheimer's disease. 137 73

Cerebral deposition of the beta-amyloid peptide (A beta) is an invariant feature of Alzheimer's disease. Since the original isolation and characterization of A beta (ref. 1) and the subsequent cloning of its precursor protein, no direct evidence for the actual production of discrete A beta has been reported. Here we investigate whether A beta is present in human biological fluids using antibodies specific for an epitope within A beta that spans the site of normal constitutive cleavage. These antibodies were used to construct a sandwich-type enzyme-linked immunosorbent assay that detects A beta in cerebrospinal fluid, plasma and conditioned medium of human mixed-brain cells grown in vitro (see also ref. 14). By affinity chromatography, we have purified and sequenced A beta and a novel A beta fragment from human cerebrospinal fluid and conditioned medium of human mixed-brain cell cultures. These findings demonstrate that A beta is produced and released both in vivo and in vitro. These observations offer new opportunities for developing diagnostic tests for Alzheimer's disease and therapeutic strategies aimed at reducing the cerebral deposition of A beta.
 ...
PMID:Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. 140 27

The distribution of beta-amyloid protein (beta A4) was examined in the medial temporal lobes from cases of Alzheimer's disease (AD) (n = 13), senile dementia of Lewy body type (SDLT) (n = 12) and age matched controls (n = 9). Using a previously described image analysis technique the extent of beta A4 pathology was determined in ten distinct anatomical sites within the medial temporal lobe. AD and SDLT cases contained very similar amounts of beta A4 in the areas sampled and both contained significantly more beta A4 than the age matched controls, particularly in the dentate and parahippocampal gyri. The similarity of the beta A4 load in the two conditions is in contrast to reported differences in the number of neurofibrillary tangles which can be observed. It is suggested that AD and SDLT represent a spectrum of pathology which centres around the aberrant processing of the beta A4 precursor protein.
 ...
PMID:Quantification of beta A4 protein deposition in the medial temporal lobe: a comparison of Alzheimer's disease and senile dementia of the Lewy body type. 140 27

During recent years, Alzheimer's disease (AD) has attracted increasing interest among clinicians and neuropathologists throughout the world. The amyloid core of the neuritic plaques found in the brains of individuals with the disease has been shown to be composed of a distinct peptide formed through proteolytic degradation of a large precursor protein, the Alzheimer amyloid precursor protein (APP), which exists in at least three isoforms differing from each other in the splicing of the primary transcript from which they derive. Although the physiological function of APP remains unknown, it has been suggested to function as a protease inhibitor and to be important to the blood coagulation system. The gene encoding APP is located on the long arm of chromosome 21. Individuals with Down's syndrome (trisomy 21) often develop AD in early middle age, suggesting that the 50 percent increase in APP, gene expression may promote the development of the disease. Mutations in the APP gene have also been shown to be associated, probably pathogenetically with familial forms of AD. The conclusions drawn from these studies include (i) that the amyloidosis associated with AD is probably a central pathogenetic factor and (ii) that the development of drugs capable of inhibiting amyloidosis might be an appropriate strategy for the treatment of AD.
 ...
PMID:[Alzheimer's disease--an amyloid disease of the brain]. 146 Oct 50

The cellular pathology of Alzheimer's disease includes an accumulation of microglia surrounding the amyloid plaques. We report that human amyloid beta-protein is chemotactic for murine resident peritoneal macrophages and rat microglia, which may account for the increased density of microglia in plaques. A maximal chemotactic response was observed at 1-10nM, with a 2.5 fold increase in activity over controls for both classes of mononuclear phagocytes. The neurotoxic peptide fragment (25-35) of amyloid beta-protein is similarly chemotactic, while a control scrambled version and the precursor protein are not chemotactic. These results indicate that beta-protein may influence plaque formation via the recruitment of phagocytes, with consequent implications for the future development of treatments for Alzheimer's disease.
 ...
PMID:The amyloid beta-protein of Alzheimer's disease is chemotactic for mononuclear phagocytes. 147 19

beta-Amyloid peptide is the major protein component of senile plaques and cerebrovascular amyloid deposits in patients with Alzheimer's disease. The peptide deposits extracellularly in the form of amyloid fibrils, in a cross-beta conformation. beta-amyloid peptide is a 39- to 43-residue segment of a normal membrane precursor protein. In this work, a peptide homologous to the first 40 amino acids of beta-amyloid peptide, beta(1-40), was synthesized and characterized. beta(1-40) exhibited a sharp change in solubility near physiological pH and gel formation at concentrations of 3 mg/ml or greater. Circular dichroism indicated that beta(1-40) contained approximately two-thirds beta-structure, but no alpha-helical character. Quasi-elastic and classical light scattering measurements showed that beta(1-40) aggregated end-to-end in solution, reaching average molecular weights greater than 4 x 10(6) after 13 days. The aggregates were best modeled as rigid rods of 5 nm diameter, similar to the diameter of amyloid fibrils purified from plaques. A mathematical model based on diffusion-limited aggregation was developed to describe the kinetics of aggregation.
 ...
PMID:Kinetics of aggregation of synthetic beta-amyloid peptide. 156 17

Considerable evidence suggests that in Alzheimer's disease, olfactory bulb damage may be a primary factor, causing degeneration and neurofibrillary tangles primarily in neurons connected with this brain area. Also, deposits of amyloid may involve an improper regulation of the cleavage of a precursor protein by glia. Finally, toxic effects of aluminium may be an etiological factor. This review proposes that all these seemingly unrelated aspects of Alzheimer's disease could be related to a disturbed function of metal-containing glia. Such a disturbance, initiated by or aggravating toxic effects of aluminum, may underlie initial damage in the olfactory bulb and/or other brain areas with a weakened blood-brain barrier and may be responsible for amyloid deposition.
 ...
PMID:Alzheimer's disease and metal-containing glia. 161 54

Alzheimer's disease (AD) is the most frequent cause of dementia, although no genetic abnormality has been identified. Recent studies have elucidated the molecular defect in AD, including the abnormal deposition of amyloid beta peptide (beta/A4) in senile plaques of affected individuals. Normal brain contains the enzyme, APP secretase, which cleaves inside the beta/A4 portion of the precursor protein (APP); abnormal processing of APP occurs in AD brain. Until now, no evidence has been provided that APP secretase is an intracellular proteinase. We have now prepared two synthetic substrates of APP secretase, both of which contain the cleavage point and are much more sensitive than substrates previously available to identify APP secretase. Using these substrates, we found an intracellular proteinase that has APP secretase activity. This proteinase has been identified as cathepsin B.
 ...
PMID:Alzheimer's disease amyloid beta-clipping enzyme (APP secretase): identification, purification, and characterization of the enzyme. 164 61


1 2 3 4 5 6 7 8 9 10 Next >>